Chemical method

FIELD: chemistry.

SUBSTANCE: present invention relates to a method for synthesis of a compound of formula I , in which X1 is selected from O; and X2 is N; involving successive reaction of a formula II compound with (i) methyl- or optionally substituted aryl-lithium; then (ii) n-butyl-, sec-butyl-, tert-butyl- or n-hexyl-lithium; and then (iii) borate ester. The invention also relates to a method of obtaining formula IV compounds: , which involves combination of [4-(1,3,4-oxadiazol-2-yl)phenyl]boronic acid with a formula III compound, in which P is a nitrogen protecting group, and to a formula IV compound, where P is C1-6alkoxycarbonyl.

EFFECT: design of an efficient method of obtaining the said compound.

9 cl, 9 ex

 

The present invention relates to an improved chemical process for the preparation of intermediate compounds. Some of these intermediate compounds suitable for the preparation of compounds that are used to treat, for example, malignant neoplasms, pain and cardiovascular diseases in a warm-blooded animal, such as man, preferably compounds which have an antagonistic effect against the endothelin receptor.

In particular, the present invention relates to a chemical process for the preparation of [4-(1,3,4-oxadiazol-2-yl)phenyl]Bronevoy acid, which is used for cookingN-(3-methoxy-5-methylpyrazine-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyridine-3-sulfonamida that described in example 36 international patent application WO 96/40681. This compound has an antagonistic effect against the endothelin receptor and, therefore, useful in cases when you need such antagonistic activity, in particular for research purposes in pharmacology, diagnostic tools, and for similar research or for the treatment of diseases and pathological conditions, including, but not limited to, hypertension, pulmonary hypertension, a disease with cardiac or cerebral circulatory and kidney disease. To the ome, this compound is also suitable for the treatment of malignant neoplasms and pain in a warm-blooded animal such as man.

The way to getN-(3-methoxy-5-methylpyrazine-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyridine-3-sulfonamida described in international patent applications WO 96/40681 and WO 98/40332. In this way use the compound N-(isobutoxide)-2-(4-ethoxycarbonylphenyl)-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide as an intermediate product for the formation of 1,3,4-oxadiazole in the 4th position of the phenyl group, what happens at the end of the synthesis. This path is successful for the synthesis of relatively small quantities ofN-(3-methoxy-5-methylpyrazine-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl) pyridine-3-sulfonamida, but he is more linear than the convergent synthesis, including the allocation of significant amounts of intermediate compounds. The total yield of this synthesis is essentially is not large.

In addition, since the formation of the heteroaryl part in the 4th position of the phenyl group is at the last stage, there is a need to use the linear approach of synthesis with the rest of the molecule, which was obtained earlier. This approach is highly undesirable, if the substituents in different parts of the molecule must change to ensure the possibility of the particular study of the relationship between structure and activity. Highly desirable is to develop a convergent approach to the synthesis of compounds of this type. Also its great advantage will be gettingN-(3-methoxy-5-methylpyrazine-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl) pyridine-3-sulfonamida in large quantities.

Now we have developed a greatly improved method of obtaining heteroaryl-phenyl-Baranovich acids, in particular [4-(1,3,4-oxadiazol-2-yl)phenyl]Bronevoy acid. This method allows the use of a convergent path forN-(3-methoxy-5-methylpyrazine-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyridine-3-sulfonamida compared with the previously described way and to ensure the decrease of intermediate products that you want to select. This provides a significant advantage with respect to the time and cost of obtaining it.

In a further embodiment, the present invention one of heteroaryl-phenyl-Baranovich acid, [4-(1,3,4-oxadiazol-2-yl)phenyl]baronova acid obtained in accordance with the present invention, is used to obtain the N-protectedN-(3-methoxy-5-methylpyrazine-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyridine-3-sulfonamide, in particularN(isobutoxide)N-(3-methoxy-5-methylpyrazine-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl) pyridine-3-sulfonamida. Then these intermediate compounds m is tenderly to remove protection gettingN-(3-methoxy-5-methylpyrazine-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyridine-3-sulfonamide.

In the method of obtaining heteroaryl-phenyl-Baranovich acids according to the present invention using the increased acidity of the proton heteroaryl ring and provide for consistent application of two reasons. Initial attempts at adding one equivalent of base to heteroaryl-phenyl-bromine compound to stimulate the exchange of halogen to metal led to the complete deprotonation heteroaryl ring. When quenched using complex borate ester was obtained the desired product with little output, together with the starting material and by-products. The authors of the present invention unexpectedly found that the successive application of two bases leads to obtaining the required heteroaryl-phenyl-Baranovich acids in good yield. In the method according to the present invention, first, a heteroaryl ring deprotonated with (usually) a "less strong" basis, then induce the exchange of halogen to metal (usually) "stronger" basis.

In accordance with the first embodiment of the present invention provides a method of obtaining the compounds of formula I

in which

X1selected from O, NR1or S;

X2SEL is given from CH or N,

where R1represents azatadine group,

which includes:

sequential interaction of the compounds of formula II

with

(i) methyl, or optionally substituted abilities; and then

(ii) n-butyl, sec-butyl, tert-butyl or n-hexyllithium; and then

(iii) a complex borate ether.

For stages (i), (ii) and (iii) how the reaction is suitably can be performed in an inert solvent or diluent, or an ethereal solvent such as diethyl ether, tetrahydrofuran, diethoxymethane, 1,2-dimethoxyethane or 1,4-dioxane. Therefore the reaction can be performed, for example, by sequential processing of 2-(4-bromophenyl)-1,3,4-oxadiazole 4-methylphenylethyl, then n-hexyllithium and in the end triisopropylsilane in a suitable solvent or diluent, for example in an ether solvent such as tetrahydrofuran, at a temperature in the range of, for example, from -90 to -50°C, more preferably from -70°C to -55°C, suitably at -70°C. or about 70°C.

Optional heteroaryl-phenyl-bromine compound of the formula II can be loaded with a solution of the first base to allow deprotonation followed by the addition of the second grounds for invoking Parametrierung. This method although it is slightly less efficient in its output and ka is estu, but it has advantages in cases where the first substrate must be formed in situ due to insufficient stability at ambient temperatures. In this case, to complete processing requires only one low-temperature vessel.

The molar ratio of the reagents that are used in the stages (i), (ii) and (iii) of the method, preferably in the range 1,0-1,5:1,0-1,5:2,1-3 respectively, but more preferably in the range 1,06-1,3:1,07-1,1:2,2-2,3 respectively. Suitably formed by ion intermediate in the conversion of compounds of formula II into compounds of the formula I as such are not allocated, but each of them is received and used in the form of a solution in an organic solvent. Thus, the compounds of formula I can be obtained from compounds of formula II by methods in the same vessel.

Ability represents, for example, phenyl or naphtalite.

Optional Deputy for argillite represents, for example, methyl.

Preferred optionally substituted arylidene are, for example, phenyl-, 2-were-, 4-were-mesityl or naphtalite.

Complex borate ester is alkyl, alkanniny or aryl baranovy ester, for example, trimethyl-, triethyl - or triisopropyl-Borat.

If R1the submitted is azatadine group, the appropriate methods for protection are, for example, methods known to the person skilled in the art. Suitable protective groups can be used according to common practice (for illustration see T.W.Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991).

Suitable azatadine group R1is, for example, C1-C6-alkyl, phenyl, allyl, methoxymethyl, benzyl, triphenylmethyl or diphenylphosphinyl protective group.

In this first embodiment of the present invention are provided compounds of the formula I in commercially acceptable yields and high quality.

Further values of X1and X2the following values are. Such values can be used if it is appropriate, in accordance with any of the definitions, claims or variants of the invention, mentioned previously in the present invention or in the future.

X1represents O.

X1represents NR1.

X1represents S.

X2represents CH.

X2represents N.

X1represents O, and X2represents CH.

X1represents O, and X2represents N.

X1and X2represent N.

X1not only is em a NR 1and X2represents CH.

X1represents NR1, a X2represents N.

X1represents S, and X2represents CH.

X1represents S, and X2represents N.

R1represents allyl or benzyl.

R1represents benzyl.

Therefore, in an additional embodiment, the invention provides a method of obtaining compounds of formula I

in which

X1selected from O, NR1or S;

X2selected from CH or N;

where R1represents azatadine group;

which includes

sequential interaction of the compounds of formula II

with

(i) 4-methylphenylethyl; and then

(ii) n-hexyllithium; and then

(iii) triisopropylsilane.

In a further embodiment, the invention provides a method of obtaining compounds of formula I

in which

X1selected from O, NR1or S;

X2selected from CH or N,

where R1represents azatadine group,

which includes:

sequential interaction of the compounds of formula II

with

(i) methyllithium; and then

(ii) n-gecsi is lithium; and then

(iii) triisopropylsilane.

In a further embodiment, the invention provides a method of obtaining compounds of formula I

in which

X1represents O; and

X2represents N,

which includes:

sequential interaction of the compounds of formula II

with

(i) methyllithium; and then

(ii) n-butyllithium; and then

(iii) triisopropylsilane.

In a further embodiment, the invention provides a method of obtaining compounds of formula I

in which

X1represents O; and

X2represents N,

which includes:

sequential interaction of the compounds of formula II

with

(i) 4-methanolica; and then

(ii) n-butyllithium; and then

(iii) triisopropylsilane.

The compounds of formula (II) can be obtained according to experimental methods and techniques described in Bioorganic & Medicinal Chemistry Letters, 2002, 12(20), 2879-2882; Eur. J. Med. Chem., 2000, 35, 157-162; Helvetica Chimica Acta, 1950, 33, 1271-1276; Eur. J. Med. Chem., 1985, 20(3), 257-66 and J. Het. Chem., 1989, 26, 1341.

In a further embodiment, the present invention provides the use of [4-(1,3,4-oxadiazol-2-yl)phenyl]Bronevoy acid obtained in accordance with h is a worthwhile invention, to obtain the compounds of formula IV, which are intermediates useful for gettingN-(3-methoxy-5-methylpyrazine-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyridine-3-sulfonamida.

N-(3-Methoxy-5-methylpyrazine-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyridine-3-sulfonamide are obtained by removing protection from compounds of formula IV.

In this embodiment of the invention [4-(1,3,4-oxadiazol-2-yl)phenyl]Bronevoy acid combine with the compounds of the formula III to form compounds of formula IV.

Preferably this reaction is carried out in an aqueous solvent, for example methanol, ethanol, isopropanol, industrial methylated spirit (IMS), isobutyl alcohol, NMP (N-methylpyrrolidinone), DMF; with an organic phase or without it, for example toluene or xylene, at a temperature in the range of, for example, from 60 to 100°C., more preferably from 75 to 85°C., in the presence of:

(i) Bronevoy acids;

(ii) a suitable source of palladium (0), for example PdCl2Pd(Ph3P)4or Pd(OAc)2;

(iii) a suitable ligand, such as triphenylphosphine or trinational salt 3,3',3"-fosfomitina Tris(benzosulfimide acid);

(iv) a base, such as triethylamine, benzyldimethylamine, N-methylmorpholine, N-methylpiperidine, triethanolamine, ethyldiethanolamine, diisopropylethylamine, acetate Kali is, of cesium fluoride or potassium fluoride.

Suitable palladium source is palladium acetate.

The preferred base is N-methylmorpholine. In another embodiment, the preferred base is triethylamine.

Preferably, this reaction is carried out in water without organic solvent phase. In another embodiment, preferably this reaction is carried out in an aqueous solvent with an organic phase. If this reaction is carried out in an aqueous solvent with an organic phase, the organic phase preferably contains toluene. In another embodiment of the present invention, if the reaction is carried out in an aqueous solvent with an organic phase, the organic phase preferably contains xylene.

In another embodiment, this reaction is more preferably carried out in the presence of palladium acetate, trinitarios salt 3,3',3"-fosfomitina Tris(benzosulfimide acid), N-methylmorpholine in water and isopropanol.

In another embodiment, this reaction is more preferably carried out in the presence of palladium acetate, trinitarios salt 3,3',3"-fosfomitina Tris(benzosulfimide acid), triethylamine, xylene, water, and IMS.

The molar ratio of the reagents, which are used in the stages (i), (ii), (iii) and (iv) the way that site is preferably is in the range 1,0-2,0:0,02-0,3:0,06-0,9:1,5-5,0 accordingly, but more preferably in the range of 1,4-1,6:0,03-0,1:0,09-0,3:2,0-3,0 respectively.

In compounds of formula III or formula IV, R is azatadine group. Appropriate remedies are methods known to the person skilled in the art. In accordance with conventional practice can be a suitable protective group (for illustration see T.W.Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991).

A suitable value for R is, for example, acyl group, for example, C1-6alcoolica group, such as acetyl; arolina group such as benzoyl;

C1-6alkoxycarbonyl group, for example methoxycarbonyl, ethoxycarbonyl, solutionline or tert-butoxycarbonyl group; armletaccessory group, such as benzyloxycarbonyl; Gostinichnaya group, such as diphenylphosphinyl; benzyl group or2-6Alchemilla group, such as allyl.

A suitable value for R is C1-6alkoxycarbonyl group. More preferred values for R are methoxycarbonyl, ethoxycarbonyl or solutionline group. The most preferred value for R is isobutoxide.

Conditions unprotect for azatadine groups described in the present invention, necessarily depend on the choice of protective GRU is dust. Thus, for example, acyl group, such as C1-6alcoolica or C1-6alkoxycarbonyl group, or arolina group may be removed, for example, by hydrolysis with a suitable base, such as hydroxide of alkali metal such as lithium hydroxide or sodium or an amine, such as ammonia. Alternatively, alkoxycarbonyl group, such as tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid, such as hydrochloric, sulphuric or phosphoric acid or triperoxonane acid, and armletaccessory group, such as benzyloxycarbonyl group may be removed, for example by hydrogenation in the presence of a catalyst such as palladium on charcoal, or by treatment with Lewis acid such as Tris(trifurcation) boron. Gostinichnaya group can be removed by hydrolysis using an alkali such as an alkali metal hydroxide such as lithium hydroxide, or sodium or an amine, such as ammonia. Benzyl group can be removed by hydrogenation in the presence of a catalyst such as palladium on coal. With2-6Alchemilla group, such as allyl, can be removed by hydrolysis using palladium.

In a further embodiment, the invention provides a method of obtaining the compounds of formula IV, which which includes interaction [4-(1,3,4-oxadiazol-2-yl)phenyl]Bronevoy acid with the compound of the formula III.

In a further embodiment, the invention provides a method of obtaining the compounds of formula IV, which includes the interaction [4-(1,3,4-oxadiazol-2-yl)phenyl]Bronevoy acid obtained according to the present invention, with a compound of formula III.

In this embodiment of the invention, more preferably the invention provides the use of [4-(1,3,4-oxadiazol-2-yl)phenyl] Bronevoy acid obtained according to the present invention, to obtainN(isobutoxide)N-(3-methoxy-5-methylpyrazine-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyridine-3-sulfonamida, the compounds of formula IV and an intermediate connection, suitable forN-(3-methoxy-5-methylpyrazine-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyridine-3-sulfonamida.

In this embodiment of the invention [4-(1,3,4-oxadiazol-2-yl)phenyl]Bronevoy acid are combined withN(isobutoxide)-2-chloro-N-(3-methoxy-5-methylpyrazine-2-yl) pyridine-3-sulfonamide with gettingN(isobutoxide)N-(3-methoxy-5-methylpyrazine-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyridine-3-sulfonamida.

GettingN(isobutoxide)-2-chloro-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamida described in example 1 application WO 96/40681.

Thus, according to this variant embodiment of the invention provides methods for the get N(isobutoxide)N-(3-methoxy-5-methylpyrazine-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyridine-3-sulfonamida, which includes a combination of [4-(1,3,4-oxadiazol-2-yl)phenyl]Bronevoy acidN(isobutoxide)-2-chloro-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide.

Therefore, in a further embodiment, the invention provides the use of [4-(1,3,4-oxadiazol-2-yl)phenyl]Bronevoy acid to obtainN(isobutoxide)N-(3-methoxy-5-methylpyrazine-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyridine-3-sulfonamida.

In a further embodiment, the invention provides the use of [4-(1,3,4-oxadiazol-2-yl)phenyl]Bronevoy acid obtained in accordance with the method of the present invention, to obtainN(isobutoxide)N-(3-methoxy-5-methylpyrazine-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl) pyridine-3-sulfonamida.

In a further embodiment, the invention provides a compound of formula IV.

In a further embodiment, the invention providesN(isobutoxide)N-(3-methoxy-5-methylpyrazine-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyridine-3-sulfonamide.

In a further embodiment, the invention provides the use ofN(isobutoxide)N-(3-methoxy-5-methylpyrazine-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)is iridin-3-sulfonamida to get N-(3-methoxy-5-methylpyrazine-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyridine-3-sulfonamida.

Further, the invention is illustrated by the following examples which do not limit its scope and in which, unless expressly stated otherwise:

(i) the outputs are presented only to assist the reader and not necessarily that they can to get the maximum with careful implementation of the method;

(ii)1H NMR spectra were determined at 270 MHz or 400 MHz in MCOd6using tetramethylsilane was (TMS) as internal standard, and expressed as chemical shifts (Delta values) in common. per million relative to TMS using conventional abbreviations for designation of major peaks: s, singlet; m, multiplet; t, triplet; br, broad; d, doublet.

Example 1

[4-(1,3,4-oxadiazol-2-yl)phenyl]baronova acid

The solution metallyte (8 wt.% in diethoxymethane) (65 ml) was added to a suspension of 2-(4-bromophenyl)-1,3,4-oxadiazole (40 g) in tetrahydrofuran (THF) (415 ml) at -65°C. Then after 1 hour, the solution was added n-utility (2,5M in hexano) (78 ml) at -65°C. Then after 1 hour was added triisopropylsilyl (90 ml), maintaining the reaction mixture at -65°C. the Reaction mixture was stirred at -65°C. for one hour and then was heated to -20°C and immersed in a mixture of acetic acid (28 ml) in water (222 ml). The obtained solid was isolated, washed with THF and water, and dried, is the learn specified in the title compound (of 28.96 g @ 95,1 wt.%, 82%); 400 MHz NMR spectrum: (MCOd6) 8,00 (s, 4H), 8,31 (s, 2H), 9,35 (s, 1H). Mass spectrum MH+191,0628 (calculated using the 11-In) Detected 191,0633.

2-(4-Bromophenyl)-1,3,4-oxadiazol used as the starting material, was prepared as follows.

To a suspension of 4-brombenzene hydrazide (200 g) in industrial methylated alcohol (700 ml) was added triethylorthoformate (309 ml), industrial methylated spirit (100 ml) and sulfuric acid (0.8 ml). The reaction mixture was heated in a flask under reflux for 1 hour. The reaction mixture was cooled to 0-5°C and the product crystallized. The product was isolated, washed and dried, obtaining 2-(4-bromophenyl)-1,3,4-oxadiazol (186,1 g, 89.9 percent). 400 MHz NMR spectrum: (MCOd6) a 9.35 (s, 1H), 7,98 (d, 1H), 7,95 (d, 1H), to 7.84 (d, 1H), 7,81 (d, 1H). Mass spectrum MH+224,9663 (calculated using the 79-VG) Found 224,9701.

Example 2

[4-(1,3,4-oxadiazol-2-yl)phenyl]baronova acid

Granules lithium (8,2 g) and tetrahydrofuran (670 g) were loaded into the reactor in an argon atmosphere and the mixture was cooled to -35°C. was Added 4-chlorotoluene (74,3 g) at -35°C and the mixture was stirred at this temperature for 6 hours. The resulting solution was added to a suspension of 2-(4-bromophenyl)-1,3,4-oxadiazole (to 124.4 g) in tetrahydrofuran (800 g) at -65°C. and Then 30 minutes later was added a solution of n-hexolite (33 wt.% in hexano) (240 ml) at -65°C. Then, after 30 minutes add the eno added triisopropylsilyl (to 230.8 g), maintaining the reaction mixture at -65°C. the Reaction mixture was left to warm to -35°C and immersed in a solution of acetic acid (91,5 g) in water (688 g). The obtained solid was isolated, washed with THF and water, and dried, obtaining mentioned in the title compound (92,2 g, 88%).

Example 3

[4-(1,3,4-oxadiazol-2-yl)phenyl]baronova acid

Example 2 was repeated, but the download of 4-chlorotoluene was increased from 1.06 to 1.30 moles moles. The output specified in the title compound was increased to 89.3%.

Example 4

[4-(1,3,4-oxadiazol-2-yl)phenyl]baronova acid

Tetrahydrofuran (250 g) was loaded to the mixture of granules lithium (3,02 g) and biphenyl (0.01 g) in an argon atmosphere and the mixture was cooled to -30°C. was Slowly added 2-chlorotoluene (27,55 g) at -30°C. the Reaction mixture was kept at -30°C for 6 hours and then was cooled to -65°C. was Slowly added a mixture of 2-(4-bromophenyl)-1,3,4-oxadiazole (50.0 g) in THF (300 g) at -65°C. the Reaction mixture was stirred at -65°C for 30 minutes, then the solution was added n-hexolite (33 wt.% in hexano, 86 ml) at -65°C. the Reaction mixture was stirred at -65°C for 30 minutes and then added trimethylboron (48,7 g) at -65°C. the Reaction mixture was stirred at -65°C for 10 minutes, then added methanol (55,3 g), then 4-methyl-2-pentanon (240 g). The reaction mixture was heated and low-boiling solvents drove in vacuum to maximilianstr 55°C. The remaining mixture was cooled to 0°C was added 10 wt.% sulfuric acid (92 g), then water (92 g), while the temperature was maintained below 7°C. the Product was besieged. the pH was brought to 6.5 by further adding 10 wt.% sulfuric acid (85,3 g). The mixture was heated to 40°C, back then was cooled to 5-10°C. the Product was isolated and washed with THF (56 g) and water (60 g), getting wet specified in the title compound (25,2 g, 60%).

Example 5

[4-(1,3,4-oxadiazol-2-yl)phenyl]baronova acid

Tetrahydrofuran was downloaded to the granules lithium (7.6 g) in an argon atmosphere and the mixture was cooled to -30°C. was Slowly added 2-chlorotoluene (69,4 g) at -30°C. the Reaction mixture was kept at -30°C for 6 hours, then was added to a suspension of 2-(4-bromophenyl)-1,3,4-oxadiazole (to 124.4 g) in tetrahydrofuran (800 g) at -65°C. the Reaction mixture was stirred at -65°C for 30 minutes, then was added a solution of n-hexolite (33 wt.% in hexano, 245 ml) at -65°C. the Reaction mixture was stirred at -65°C for 30 minutes and then added trimethylboron (to 230.8 g) at -65°C. the Reaction mixture was stirred at -65°C for 30 minutes, then was added methanol (175 ml), then 4-methyl-2-pentanon (600 g). The reaction mixture was heated and low-boiling solvents drove in a vacuum to a maximum temperature of 50°C. the Reaction mixture was cooled to 5-10°C. and the pH was brought to 6.5 by adding 5 wt.% sulfuric KIS is the notes (990,5 g). The product was besieged. The mixture was heated to 40°C., then cooled back to 10°C. the Product was isolated, washed with THF and water, and dried, obtaining mentioned in the title compound (79,3 g, 75,5%).

Example 6

[4-(1,3,4-oxadiazol-2-yl)phenyl]baronova acid

Example 4 was repeated, but using chlorobenzene (61,6 g) instead of 2-chlorotoluene.

Specified in the title compound was isolated with a yield of 87.8 g (83.8 percent).

Example 7

N-(Isobutoxide) N-(3-methoxy-5-methylpyrazine-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyridine-3-sulfonamide

The palladium acetate (0,4144 g) and chinatravel salt 3,3',3"-fosfomitina Tris(benzosulfimide acid) 30 wt.% aq. rest. (3,26 g) was dissolved in water (35 ml) for 6 minutes in an ultrasonic bath. The yellow solution was added to a stirred suspension of [4-(1,3,4-oxadiazol-2-yl)phenyl]Bronevoy acid (10 g) and isobutyl [(2-chloropyridin-3-yl)sulfonyl](3-methoxy-5-methylpyrazine-2-yl)carbamate (16,86 g) in xylene (100 ml), industrial methylated spirit (50 ml) and triethylamine (17 ml). Then the flask to dissolve the catalyst was washed with water (5 ml) and the reaction mixture was heated in a flask under reflux (80°C) oil bath (105°C) and stirred in a flask under reflux in the course of 24.5 hours. The reaction mixture was cooled to 30°C. and filtered through stellwagen filter paper Whatman GF/B and the lower aqueous phase was separated is. The reaction flask and the filter residue was washed with xylene (20 ml). Xiaowei washing used for re-extraction of the aqueous phase. The combined organic phase was stirred and heated in a flask with reflux (85°C) of pure 4-necked flask of 500 ml, equipped with a pressure stirrer, water condenser and nitrogen atmosphere. Was added dropwise the solvent Essochem 30 (hydrocarbons BP 100-130°C) (100 ml) for 6 minutes and the mixture was allowed yourself to cool to ambient temperature and then further cooled to -5°C. and kept for 1 hour. The product was filtered and washed with solvent Essochem 30 (50 ml). The precipitate was dried on the filter for 3 hours, getting 15,20 g @100% concentration, the yield of 76.8%. 270 MHz1H-NMR-spectrum: 0,70 (d, 6N), 1,72 (m, 1H), of 2.51 (s, 3H), of 3.84 (d, 2H), 4.00 points (s, 3H), to 7.59 (m, 1H); 7,80 (d, 2H), of 7.90 (s, 1H), 8,17 (d, 2H), and 8.50 (s, 1H), 8,90 (m, 1H) and 9.00 (d, 1H). The mass spectrum of MN+=525,2 (C24H25N6O6S=525,16).

Example 8

N-(Isobutoxide) N-(3-methoxy-5-methylpyrazine-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyridine-3-sulfonamide

In a nitrogen purged mnogogolovy flask of 500 ml, equipped with a pressure stirrer, was loaded isobutyl [(2-chloropyridin-3-yl)sulfonyl](3-methoxy-5-methylpyrazine-2-yl)carbamate (22,15 g), [4-(1,3,4-oxadiazol-2-yl)phenyl]Bronevoy acid (of 12.26 g), isopropanol (6 ml), water (140 ml) and chinatravel salt 3,3',3"-fosfomitina Tris(benzosulfimide acid) 30 wt.% aq. rest. (of 13.7 g). He started shaking and after 10 minutes was added palladium acetate (0,541 g). Was added N-methylmorpholine (13,25 ml) and the temperature was brought to 80°C. After 4 hours, 20 minutes was added toluene (140 ml) and the temperature was brought to 60°C. Additionally, after 45 minutes the mixture was filtered through 1 μm stellwagon filter paper and the aqueous phase was separated. The reaction flask and the filter residue was washed with toluene (22 ml). Toluene wash was used for re-extraction of the aqueous phase and the organic layers were combined. They contain specified in the title compound (22,8 g, 90%), which was not identified.

Example 9

N-(Isobutoxide) N-(3-methoxy-5-methylpyrazine-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyridine-3-sulfonamide

In a nitrogen purged mnogogolovy flask with a volume of 150 ml, which is equipped with pressure stirrer, was loaded isobutyl [(2-chloropyridin-3-yl)sulfonyl](3-methoxy-5-methylpyrazine-2-yl)carbamate (of 7.75 g), [4-(1,3,4-oxadiazol-2-yl)phenyl]Bronevoy acid (4,29 g), isopropanol (21 ml), water (49 ml) and chinatravel salt 3,3',3"-fosfomitina Tris(benzosulfimide acid) 30 wt.% aq. rest. (2,88 g). He started shaking and after 10 minutes was added palladium acetate (0,114 g). Was added potassium fluoride (2,48 g) and the temperature was brought to 80°C. H is cut 5 hours was added toluene (49 ml) and the temperature was brought to 60°C. Additionally, after 10 minutes the mixture was filtered through 1 μm stellwagon filter paper and the aqueous phase was separated. The organic phase contained specified in the title compound (of 7.36 g, 83%)which was not identified.

1. The method of obtaining the compounds of formula I

in which,
X1choose from;
X2represents N;
including the sequential interaction of the compounds of formula II

with
(i) methyl, or optionally substituted abilities; and then
(ii) n-butyl, sec-butyl, tert-butyl or n-hexyl-lithium; and then
(iii) a complex borate ether.

2. The method according to claim 1, wherein said methyl or optionally substituted ability is a 4-methylphenylethyl or motility.

3. The method according to claim 1, wherein said n-butyl, sec-butyl, tert-butyl or n-exility is an n-exility or n-utility.

4. The method according to claim 1, wherein said complex borate ester is triisopropylsilyl.

5. The method of obtaining compounds of formula IV

which includes a combination of [4-(1,3,4-oxadiazol-2-yl)phenyl]Bronevoy acid with the compound of the formula III

in which R represents azatadine group.

6. The method according to claim 5, which carried the t in the presence of
(i) a source of palladium (0), selected from PdCl2Pd(Ph3P)4or Pd(OAc)2;
(ii) a suitable ligand selected from triphenylphosphine or trinational salt 3,3',3"-fosfomitina Tris(benzosulfimide acid);
(iii) a base selected from triethylamine, benzyldimethylamine, N-methylmorpholine, N-methylpiperidine, triethanolamine, ethyldiethanolamine, diisopropylethylamine, potassium acetate, cesium fluoride or potassium fluoride.

7. The method according to claim 5, in which R represents isobutoxide.

8. The compound of formula IV

in which R represents a C1-6alkoxycarbonyl.

9. The compound of formula IV of claim 8, which is N-(isobutoxide)-N-(3-methoxy-5-methylpyrazine-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyridine-3-sulfonamide.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing organoboron compounds, which can be used as components of catalyst systems in oligomerisation and polymerisation of olefin, diene and acetylene hydrocarbons, as well as in fine organic and organometallic synthesis. A method is described for producing 1-phenyl-2,3,4,5-tetraalkylborocyclopenta-2,4-dienes by reacting dialkyl substituted acetylenes with phenyldichloroborane and magnesium metal in the presence of zirconocene dichloride as a catalyst in an argon atmosphere in a tetrahydrofuran medium. The reaction time is 8 to 12 hours and total output of end products is 35 to 55%.

EFFECT: obtaining novel organoboron compounds in a single step, synthesis of which is difficult or impossible using known methods.

1 cl, 1 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel class of photosensibilisers for photodynamic therapy - N,N-difluorboryl complexes of N-(3-aryl-2H-isoindol-1-yl)-N-(3-aryl-1H-isoindol-1-ylidene)amines of general formula: , where R=H,C1-C4-alkyl, OC1-C4-alkyl, Ph, Br, as well as to method of obtaining them lying in processing of respective ligand with boron trifluoride etherate in presence of secondary or tertiary amine in boiling benzole.

EFFECT: described photosensibilisers possess high photoinduced activity and are promising for practical application in photodynamic therapy method.

2 cl, 7 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to improved method of producing complex lithium borate salt to be applied as conducting salt in electrolytes in making galvanic cells, particularly lithium-ion batteries. Parent components boric acid, oxalic acid and lithium compounds (carbonate, lithium hydroxide) taken in the equivalent ratio according to the chemical reaction equation, charged in a planetary-type mill cup and mechanically activated with centrifugal rotary acceleration 500-600 m/s2 within 15-20 seconds. Synthesis is ensured within 4-6 hours in a furnace at temperature 190-220°C. Furnace heating rate to working temperature is 15-30°C/min. The prepared salt is finished drying in a vacuum furnace, then unloaded and packed in a boxing filled with dry inert gas.

EFFECT: product with low element-impurity content.

1 cl, 1 ex, 1 tbl, 5 dwg

FIELD: chemistry.

SUBSTANCE: method involves reaction synthesis of trihydrocarbylborane and aluminium oxide from trihydrocarbylboroxine and trihydrocarbylaluminium, and differs that reaction is performed in such a way that it results in trihydrocarbylaluminium in amount 0.5 or more per one mole of aluminium oxide formed from reaction thus preventing undesired gelling.

EFFECT: there is improved industrial production method for trihydrocarbylborane, the method is characterised with a number of quality and cost advantages.

4 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention describes method of obtaining novel intermediates, which are suitable for synthesis of amino acids, used for obtaining peptide receptor modulators, for instance agonists or partial agonists of said peptide receptors. Such modulators of peptide receptors include, for instance modulators of glucagon-like peptide receptors.

EFFECT: efficiency of application for relief of diabetic condition.

3 cl, 3 ex, 2 dwg

FIELD: chemistry.

SUBSTANCE: regioselective synthesis of complex rapamycin 42-ether (CCI-779) involves: (a) acylation of 31-silyl rapamycin ether by compound of formula HOOC.CR7R8R9 or its combined anhydride, where: R7 is hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, alkinyl with 2-7 carbon atoms, -(CR12R13)fOR10, -CF3, -F or -CO2R10; R10 is hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, alkinyl with 2-7 carbon atoms, triphenylmethyl, benzyl, alcoxymethyl with 2-7 carbon atoms, chloroethyl or tetrahydropyranyl; R8 and R9 together form X; X is 2-phenyl-1,3,2-dioxaborinane-5-yl or 2-phenyl-1,3,2-dioxaborinane-4-yl, where phenyl can be optionally substituted; R12 and R13 each is independently hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, alkinyl with 2-7 carbon atoms, trifluormethyl or -F; and f=0-6; to obtain 42-ether boronate of 31-silyl rapamycin ether; (b) selective hydrolysis of 42-ether boronate of 31-silyl rapamycin ether in moderately acid environment to obtain rapamycin 42-ether boronate; and (c) diol treatment of rapamycin 42-etherboronate to obtain complex rapamycine 42-ether. Invention also claims new intermediate products applicable in this method.

EFFECT: application as antitumour medication.

48 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: described is method of obtaining cyanoborates of alkali metals of general formula M+[B(CN)4]-, where M - potassium by action of alkali metal cyanide on potassium tetrafluoroborate in conditions of hard-phase reaction, their further transformation into salts, including cyanoborate anions and organic cations, said salts can be used as ion liquids.

EFFECT: creation of efficient method of obtaining alkali metal cyanoborates.

18 cl, 26 ex, 1 tbl

FIELD: medicine, radiation therapy.

SUBSTANCE: the present innovation refers to radiosensitizers that contain as an active component halogenated derivatives of borated porphyrines that contain a great number of carboranic cells which are selectively accumulated in neoplasms' tissues in the irradiated volume and could be applied in such type of cancer therapy that include but are not restricted with boron-neutron-capturing therapy and photodynamic therapy. The present innovation , also, deals with applying these radiosensitizers for visualization of the tumor and treating the cancer.

EFFECT: higher efficiency.

35 cl, 2 dwg, 8 ex, 7 tbl

FIELD: physical analytical methods.

SUBSTANCE: invention relates to bioanalytical methods involving dye-labeled indicators. Bioanalytical method without separation is provided directed to measure analyte obtained from biological liquid or suspension, wherein are used: analyte microparticles as first biospecific reagent; and second biospecific reagent labeled with biphotonic fluorescent dye based on dipyrromethene boron difluoride containing at least one water solubility imparting group selected from ammonium salt and sulfonic or carboxylic acid alkali metal salt and at least one chemically active group selected from carboxylic acid, reactive carboxylic acid ester, carboxylic acid anhydride, maleimide, amine and isothiocyanate. In the method of invention, laser is focused onto reaction suspension and biphotonically excited fluorescence from individual microparticles (randomly flowing or oriented by pressure provided by emission of exciting laser through focal volume of laser beam).

EFFECT: increased efficiency of bioanalyses.

5 cl, 5 dwg, 5 tbl, 25 ex

FIELD: polymer materials.

SUBSTANCE: invention provides luminescent material showing semiconductor properties and being product of complex polymerization in glow discharge, which is formed as a supported polymer layer located either between electrodes or on any of electrodes. Starting pyrromethene complex is difluoroborate complex of 1,3,5,7,8-pentamethyl-2,6-diethylpyrromethene (Pyrromethene 567). Method of preparing luminescent semiconductor polymer material comprises glow-discharge polymerization for 2 to 120 min of Pyrromethene 567 vapors at temperature preferably 250-350°C, pressure 10-1 to 10-2 Pa, and discharge power 0.5-3 W. Resulting luminescent polymer is characterized by thickness preferably 0.001-10 μm, conductivity 1·10-10 to 5·10-10 Ohm-1cm-1 (20°C), luminescence emission maximum in the region of 540-585 nm at band halfwidth 55-75 nm. Polymer is obtained with quantum yield 0.6-0.8 and is designed for creation of film light-emitting devices.

EFFECT: improved performance characteristics of material.

13 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to 3,3'-bis-(3,4-dihydro-3-phenyl-2H-1,3-benzoxazin-6-yl)-1(3H)-isobenzofuranone and analogues based on phenolphthalein, formaldehyde and a primary amine of formula 1: , in which R independently represents allyl or phenyl, and to a method of synthesising the said compounds. The invention also pertains to a method of making a refractory cast or layered material based on the said compounds and laminating compositions since through thermal hardening, these compounds form a net which does not catch fire easily and is resistant to high temperatures. The said compounds can be particularly useful in making printed circuit boards.

EFFECT: obtaining fire-resistant compounds.

5 cl, 4 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula Ia: and its pharmaceutically acceptable salt, where: p equals 0 or 1; n assumes values from 1 to 3, q equals 1; R5 is selected from hydrogen, -XNR7R8, pyrimidine-C0-4alkyl, pyridine-C0-4alkyl, phenyl, C3-10cycloalkyl-C0-4alkyl and C3-6heterocycloalkyl-C0-4alkyl, where C3-6heterocycloalkyl is a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R is hydrogen or C1-4alkyl; R7 and R8 represent C1-4alkyl; R6 denotes hydrogen; or R5 and R6 together with a nitrogen atom to which they are both bonded form morpholine or piperidine; where any piperdine-C0-4alkyl, piperidine-C0-4alkyl or C3-10cycloalkyl-C0-4alkyl of substitute R5 or a combination of radicals R5 and R6 can be optionally substituted with 1-2 radicals which are independently selected from -XNR7R8 and -XOR7, the said phenyl of substitute R5 is substituted with a -XR9 group, the said C3-6heterocycloalkyl-C0-4alkyl of substitute R5 is optionally substituted with a -XOR7 group, where X is a single bond or C1-4alkylene; R7 and R8 are independently selected from hydrogen and C1-4alkyl; R9 is selected from C3-10heterocycloalkyl which is a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R is as given above; R10 denotes hydrogen; R15 is selected from halogen, C1-6alkyl and C1-6alkoxy; and R16 is selected from halogen, methoxy, nitro, -NR12C(O)R13, -C(O)NR12R12, -NR12R12, -C(O)OR12 and -C(O)NR12R13; each R12 is selected from hydrogen and C1-6alkyl; R13 is selected from phenyl, thienyl, pyrazolyl, pyridinyl or isoxazolyl, where any phenyl, thienyl, pyrazolyl, pyridinyl or isoxazolyl of substitute R13 can be optionally substituted with 1-2 radicals which are independently selected from halogen, C1-6alkyl, halogen-substituted C1-6alkyl, imidazole-C0-4alkyl, C3-10cycloalkyl, C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl; where the said C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl each represent a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R assumes values given above; and the said C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl can each be optionally substituted with 1 radical independently selected from C1-6alkyl, hydroxyl-substituted C1-6alkyl and NR7R8, where R7 and R8 assume values given above. The invention also relates to pharmaceutical compositions containing the said compounds.

EFFECT: obtaining novel compounds and compositions based on the said compounds which can be used in medicine for treating and preventing diseases or disorders associated with abnormal or uncontrolled kinase activity, particularly diseases or disorders associated with abnormal activity of kinase c-Src, FGFR3, KDR and/or Lck.

12 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a group of novel chemical compounds pharmacologically acceptable salts thereof having formula , where A represents COOH; B represents H; n equals 0; V represents -CH2-, a single bond; W represents a 5-7-member heteroaromatic group with one heteroatom selected from N, O, S which can optionally be substituted with 1-3 substitutes selected from a group of substitutes A, when V represents a -CH2-group, where if V represents a single bond, W represents a bicyclic condensed a ring -member heterocyclic group with one heteroatom selected from O, S, which can optionally be substituted with 1-3 substitutes selected from a group of substitutes A; X represents a 5-7-member heteroaromatic group with one O atom and one or two N atoms, which can optionally be substituted with 1-3 substitutes selected from a group of substitutes A; Y represents C6-C10 aryl which can optionally be substituted with 1-3 substitutes selected from a group of substitutes A, a 5-7-member heteroatomatic group with one S atom which can optionally be substituted with 1-3 substitutes selected from a group of substitutes A; Z represents C1-C8 alkyl, C3-C7 cycloalkyl which can optionally be substituted with 1-5 substitutes selected from a group of substitutes A; C6-C10 aryl which can optionally be substituted with 1-5 substitutes selected from a group of substitutes A; C6-C10 aryloxy which can optionally be substituted with 1-5 substitutes selected from a group of substitutes A, or C1-C12 aralkyl which can optionally be substituted with 1-5 substitutes selected from a group of substitutes A; group of substitutes A represents halogen, C1-C6 alkyl, halogen C1-C6 alkyl, C1-C6 alkoxy.

EFFECT: compounds exhibit inhibitory activity towards HvGR which enables their use to prepare a pharmaceutical composition used in therapy for autoimmune diseases.

33 cl, 6 tbl, 30 ex

FIELD: medicine.

SUBSTANCE: invention relates to compounds of general formula (I) and their pharmaceutically acceptable salts and pharmaceutically acceptable asters, possessing activity with respect to LXRα and/or LXRβ receptors. Compounds can be applied for treatment and prevention of diseases mediated by LXRα and/or LXRβ receptors, namely: increased level of lipids and cholesterol level, atherosclerotic diseases, diabetes, metabolic syndrome, dyslipidermia, sepsis, inflammatory diseases, pancreatitis, liver cholestasis/fibrosis, and diseases which include inflammatory component, such as Alzheimer's disease and reduced/improvable cognitive function. In general formula n represents integer number from 0 to 3; R1 is independently selected from group consisting of halogen, -CN, -NO2, -SO2Me, lower alkyl, -OR11, pyperidinyl and -N(R11)(R11), where R11 is independently selected from lower alkyl and H, X1, X2, X3 and X4 are independently selected from nitrogen and carbon, on condition that, not more than two of X1, X2, X3 and X4 can simultaneously represent nitrogen, and in case when two of X1, X2, X3 and X4 represent nitrogen, n represents 0,1 or 2; k represents integer number 0 or 1; R2 represents H; R3 represents H, lower alkyl or halogen; R4 represents aryl, heteroaryl, lower alkylaryl or lower alkylheteroaryl, each of which is optionally substituted with substituents in amount from one to five, which are independently selected from group consisting of halogen, lower alkyl, -OR41, lower alkinyl and NR42R43, where R41 represents lower alkyl, R42 and R43 independently on each other represent hydrogen or lower alkyl, or NR42R43 represents pyrrolidinyl, or R4 represents lower alkyl; R5 is selected from group, heteroaryl, consisting of and , said aryl and heteroaryl being optionally substituted in one or more positions with one or more substituents, independently selected from group consisting of H, halogen, lower alkyl and (CH2)VR53, where R51 is selected from group consisting of H, lower alkyl, lower alkenyl and lower alkylaryl, said lower alkylaryl is optionally substituted in one or more positions with one or more lower alkyl, -CN, halogen, group -COOR54 and group -CH2OR54, where R54 represents lower alkyl or H; R52 represents lower alkyl or -H; R53 represents H, lower alkyl, C3-C6-cycloalkyl, -COOR55, -N(R55)(R56), -CH2OH, -CN, CF3, -CONH2 or -CH2OR55, where R55 is independently selected from group consisting of lower alkyl, -H, -C(O)aryl or -C(O)-lower alkyl, and R56 is selected from group consisting of H, lower alkyl, -C(O)CF3, -C(O)aryl, -C(O)-lower alkyl and lower alkylaryl, and where said aryl and lower alkylaryl are optionally substituted in one or more positions with one or more lower alkyl, halogen, group COOR57 and group -CH2OR57, where R57 represents lower alkyl or -H, or R55 and R56 together with atom to which they are bound, form ring system; or R53 represents aryl, which can be optionally substituted with benzyloxy, carboxy, lower alkoxycarbonyl, hydroxy-(lower alkyl), halogen, carbamoyl, (lower alkyl)carbamoyl, di-(lower alkyl)carbamoyl, m represents integer number from 0 to 2; v represents integer number from 0 to 4; where term "lower alkyl" separately or in combination with other groups refers to branched or linear monovalent alkyl radical, containing from one to six carbon atoms, where term "aryl" separately or in combination with other groups refers to phenyl or naphthyl, and where term "hetyeroaryl" refers to aromatic 5- or 6-member ring, which can include 1-3 heteroatoms selected from nitrogen, oxygen and/or sulphur, and which can be condensed with phenyl group.

EFFECT: increase of compound application efficiency.

38 cl, 5 dwg, 137 ex

FIELD: chemistry.

SUBSTANCE: described are piperazine indoles of general formula , in which R1 represents 2-indanyl, R2 represents 1-methylpropyl, R3 and R4 together with nitrogen atoms to which they are bonded represent a morpholino group, and pharmaceutically acceptable salts thereof. Also described is a pharmaceutical composition based on formula (I) compound.

EFFECT: compounds have antagonistic effect on oxytocin receptor.

6 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1) and their pharmaceutically acceptable salts as chemokine receptor CCR3 activity modulators, a pharmaceutical composition based on the said compounds, to synthesis method and use thereof. Said compounds can be used for treating and preventing diseases mediated by chemokine receptor CCR3 activity, such as inflammatory and allergic diseases etc. In general formula , R1 represents phenyl, [1,2,4]triazolo[4,3-a]pyridinyl, thiazolo [5,4-b]pyridinyl, benzothiazolyl, benzoxazolyl, pyridinyl, where each of the said phenyl or heterocycles can be substituted with one, two or three radicals R2; R2 each independently represents (C1-C6)halogenalkyl, halogen, COOR3; CONR3R4; R3 represents H or (C1-C6)alkyl; R4 represents H or (C1-C6)alkyl, R5 represents (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl; R6 each independently represents (C1-C6)alkoxy, (C1-C6)halogenalkyl, halogen, OR3, CN, CONR3R4; A represents C(CH3)2-CH2-CH2-, CH2-CH2-CH2- or B represents phenyl; D-E represents CH-CH2- or C=CH-, X-W-V represents N-C=CR7 or C=C-NR7; R7 represents H or (C1-C6)alkyl; Y represents NR4, O, S(O)n; i, j, m each equals 1, n equals 0 or 2.

EFFECT: increased effectiveness of using said compounds.

13 cl, 37 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula I and their pharmaceutically acceptable salts which have inhibitory properties towards mGluR5. In formula I , P represents phenyl; R1 is bonded to P through a carbon atom on ring P and is selected from a group consisting of halogen, C1-6alkylhalogen, OC1-6alkylhalogen, C1-6alkyl, OC1-6alkyl and C0-6alkylcyano; X1 is selected from a group consisting of N, NR4 and CR4; X2 is selected from a group consisting of C and N; X3 is selected from a group consisting of N and O; X4 is selected from a group consisting of N and O; X5 is selected from a group consisting of a bond, CR4R4', NR4, O, S, SO, SO2; X6 represents N; X7 is selected from a group consisting of C and N; Q represents triazolyl.

EFFECT: invention also relates to a pharmaceutical composition containing a therapeutically effective amount of the disclosed compound as an active ingredient, use of the compound in making a medicinal agent for treating disorders mediated by mGluR5 and to a method of inhibiting activation of mGluR5 receptors.

25 cl, 82 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a morpholine type cinnamide derivative with general formula I or its pharmacologically acceptable salt, where (a) R1, R2 , R3 and R4 are identical or different and each represents a hydrogen atom or C1-6alkyl group; X1 represents a C1-6alkylene group, where the C1-6alkylene group can be substituted with 1-3 hydroxyl groups or C1-6alkyl groups, or a C3-8cycloalkyl group formed by two C1-6alkyl groups all bonded to the same carbon atom of the C1-6alkylene group; Xa represents a methoxy group or a fluorine atom; Xb represents an oxygen atom or a methylene group, under the condition that Xb represents only an oxygen atom when Xa represents a methoxy group; and Ar1 is an aryl group, pyridinyl group which can be substituted with 1-3 substitutes selected from A1 group of substitutes; (b) Ar1-X1- represents a C5-7cycloalkyl group condensed with a benzene ring, where one methylene group in the C5-7cycloalkyl group can be substituted with an oxygen atom, the C5-7cycloalkyl group can be substituted with 1-3 hydroxyl groups and/or C1-6alkyl groups, and R1, R2, R3, R4, Xa and Xb assume values given in (a); (d) Ar1-X1- and R4 together with the nitrogen atom bonded to the Ar1-X1- group and the carbon atom bonded to the R4 group form a 5-7-member nitrogen-containing heterocyclic group which is substituted with an aryl group or a pyridinyl group, where one methylene group in the 5-7-member nitrogen-containing heterocyclic group can be substituted with an oxygen atom, and the aryl or pyridinyl group can be substituted with 1-3 substitutes selected from A1 group of substitutes, Xb is an oxygen atom, and R1, R2, R3 and Xa assume values given in (a) and (b); group A1 of substitutes: (1) halogen atom. The invention also relates to a pharmaceutical composition containing a formula I compound, which is useful in treating Alzheimer's disease, senile dementia, Down syndrome or amyloidosis.

EFFECT: obtaining novel morpholine type cinnamide derivatives with inhibitory effect on amyloid-β production.

17 cl, 9 tbl, 113 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound of formula (I) or to salts thereof: , where R1 is a hydrogen atom, amino group, R11-NH-, where R11 is a C1-6alkyl group, hydroxy-C1-6alkyl group, C1-6alkoxycarbonyl-C1-6alkyl group, R12-(CO)-NH-, where R12 is a C1-6alkyl group or C1-6alkoxy-C1-6alkyl group, C1-6alkyl group, hydroxy-C1-6-alkyl group, C1-6alkoxy group or C1-6alkoxy-C1-6alkyl group; R2 is a hydrogen atom, C1-6alkyl group, amino group or di-C1-6alkylamino group; one of X and Y represents a nitrogen atom, while the other represents a nitrogen or oxygen atom; ring A is a 5- or 6-member heteroaryl ring or benzene ring which can have 1 or 2 halogen atoms; Z is a single bond, methylene group, ethylene group, oxygen atom, sulphur atom, -CH2O-, -OCH2-, -NH-, -CH2NH-, -NHCH2-, -CH2S- or -SCH2-; R3 is hydrogen or a halogen atom, or C1-6alkyl group, C3-8cycloalkyl group, C6-10aryl group, 5- or 6-member heteroaryl group, where these groups can have 1 or 2 substitutes selected from a group of α substitutes: and [group of α substitutes] group of α substitutes is a group consisting of a halogen atom, cyano group, C1-6alkyl group, C1-6alkoxy group, C1-6alkoxycarbonyl group, C3-8cycloalkyl group, C1-6alkenyl group and C1-6alkynyl group; R4 is a hydrogen atom or halogen atom; except compounds in which all of R1, R2 and R4 represent a hydrogen atom while Z represents a single bond or R3 is a hydrogen atom; as well as a pharmaceutical composition and a medicinal agent with antifungal activity, based on these compounds, to an antifungal agent and use of formula I compounds for preparing an antifungal agent.

EFFECT: novel compounds with excellent antifungal effect are obtained and described.

36 cl, 228 ex, 8 tbl

FIELD: medicine.

SUBSTANCE: invention refers to compounds of formula I or formula II, to their pharmaceutically acceptable salts, enantiomers and diastereoisomers as metalloprotease inhibitors, and also to a pharmaceutical composition based thereon and to versions of application thereof. Said compounds can find application in treatment of the diseases mediated by activity of metalloproteases, Her-2 SHEDDASE, ADAM-10 and ADAM-17, such as arthritis, cancer, cardiovascular disorders, skin diseases, inflammatory and allergic conditions, etc. In general formula I or II: A represents CWNHOH; B represents CH2; G represents CH2; D represents oxygen; X represents CH2NRb; Y represents CH2; M represents C; U is absent or represents NRb; V is absent or represents phenyl, or 4-10-members heterocyclyl containing 1-2 heteroatoms chosen from N and S, substituted with 0-5 groups Re; U' is absent or represents C1-10alkylene, O or combinations thereof; V' represents H, C1-8alkyl, NRbRc, C6-10carbocyclyl substituted with 0-3 groups Re, or 5-14-members heterocyclyl containing 1-3 heteroatoms chosen from N, O and C substituted with 0-4 groups Re; Ra and Re, independently represents H, T, C1-8alkylene-T, C(O)NRa'(CRb'Rc')r-T, (CRb'Rc')r-O-(CRb'Rc')r-T, OH, Cl, F, CN, NO2, NRIRII, COORIV, ORIV, CONRIRII, C1-8halogenalkyl, C3-13carbocyclyl; Rb and Rc independently represents H, T, C1-6alkylene-T, C(O)O(CRb'Rc')r-T, C(O)(CRb'Rc')r-T, S(O)p(CRb'Rc')r-T; T represents H, C1-10alkyl substituted with 0-1 groups Rb'; C3-6carbocyclyl, 5-6-members heterocyclyl containing one oxygen atom; Ra' Rb' and Rc' independently represents H, ORIV or phenyl; R1 represents hydrogen; R2 represents hydrogen; R3 represents: (i) C1-10alkyl; (ii) 4-14-members heterocyclyl containing 1-3 nitrogen atoms optionally substituted with one or two substitutes chosen from C1-6alkyl, OR13, 5-10-members heterocyclyl containing 1-3 heteroatoms chosen from N O and C, or phenyl; (iii) NR16R17; R4 represents H; R4' represents H; R5' represents H; W represents oxygen; R13 represents C1-C6alkyl; R16 and R17 independently represents C1-C10alkyl or phenyl where each is optionally substituted with one C1-4alkyl; RI and RIIindependently represents H or C1-6alkyl; RIV represents C1-6alkyl; i is equal to 0; p is equal to 1 or 2 and r is equal to 0, 1 or 2; provided that a) a spiro ring represents a stable chemical base unit and b) NR8 and NRb do not contain neither N-N, nor N-O bonds.

EFFECT: higher efficiency of the composition and method of treatment.

54 cl, 1 tbl, 9 dwg, 284 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivatives of phenylpiperazine of the formula (I): , wherein X represents 1) group of the formula (1): , wherein S1 means hydrogen, halogen atom; S2 and S3 mean independently of one another hydrogen atom, (C1-C6)-alkyl, phenyl or benzyl; S4 means two hydrogen atoms, oxo-group; S5 means hydrogen atom (H), (C1-C4)-alkyl; Y means CH2, oxygen atom (O), sulfur atom (S); or 2) group of the formula (2): , wherein S1 has above given values; R means hydrogen atom (H), (C1-C4)-alkyl, (C2-C6)-alkoxyalkyl, (C2-C4)-alkenyl or (C2-C4)-alkynyl; or 3) group of the formula (3): wherein S1 has above given values; Z means CH2, oxygen atom (O), nitrogen atom (N); or 4) group of the formula (4): , wherein S1 has above given values; or 5) group of the formula (5): , wherein S1 has above given values; A means oxygen atom (O), nitrogen atom (N) linked with piperazine ring at position 5 or 8; or 6) group of the formula (6): , wherein S1 has above given values; S6 and S7 mean hydrogen atom or oxo-group; or 7) group of the formula (7): , wherein one of dotted line can represent a double bond; S1 has above given values; P = T = Q mean nitrogen atom or P = T mean nitrogen atom; Q means CH or CH2; or P = Q mean nitrogen atom; T means CH, CH2, CH-CH3, C-CH3; or P means nitrogen atom; T means CH, CH2; Q represents sulfur atom; m = 2-6; n = 0-2; R5 and R6 mean independently of one another hydrogen atom (H), (C1-C3)-alkyl; or R5 + R6 represent group -(CH2)p- wherein p = 3-5; R7 means (C1-C3)-alkyl, (C1-C3)-alkoxy-, halogen atom, cyano-group; or R6 + R7 (R7 at position 7 of indole ring) mean group -(CH2)q wherein q = 2-4, and their salts. Compound of the formula (I) elicit high affinity both to dopamine D2-receptor and to serotonin reuptake site that allows their applying in treatment of the central nervous system diseases.

EFFECT: valuable medicinal properties of compounds.

5 cl, 3 tbl, 4 sch, 8 ex

Up!